Documentation / Structural Variants / Interpretation

Interpretation and Limitations

Folklore separates event normalization, evidence annotation, framework ownership, and verdict assembly. This makes it possible to distinguish what the VCF reported, what reference data contributed, and which interpretation framework produced the displayed result.

Evidence Reviewed

Genomic content

Event span, affected genes and exons, and whether breakpoints or the full interval overlap an annotated gene region.

Dosage sensitivity

Curated ClinGen haploinsufficiency and triplosensitivity regions, plus locally available predicted dosage-sensitivity evidence.

Population evidence

Type-compatible structural-variant overlap against local gnomAD SV/CNV references. A true absence is kept distinct from a record that could not be annotated.

Call confidence

Precision status, breakpoint confidence intervals, paired-read and split-read support, and related fields when supplied upstream.

Inheritance and phenotype

Relevant only when the submitted data and current schema provide sufficient evidence. Missing segregation or phenotype specificity is not silently assumed.

Copy-Number Classification

Constitutional copy-number losses and gains are evaluated with the applicable ClinGen/ACMG Riggs 2020 evidence framework. When sufficient evidence is available, the result uses the standard five tiers: Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign, or Benign.

The result view identifies the applied criteria, whether each reviewed criterion contributed, the total used by the framework, and the final tier. Folklore exposes this audit trail without publishing implementation-specific optimization or internal scoring code.

A Structural Type Does Not Guarantee a Riggs Verdict

Riggs 2020 ownership is reserved for constitutional copy-number loss and gain. Other eligible nuclear structural events may enter the nuclear Variant Analysis framework, while records without a safe owner retain no automated verdict and a reviewable reason.

Missing Evidence and Safe Under-Calling

Unavailable evidence does not receive a favorable or pathogenic contribution by default.

Incomplete breakpoint geometry can prevent reliable gene, exon, or region overlap assessment.

Insertions and breakends without an end coordinate have limited interval-based annotation.

The current structural schema cannot establish every inheritance, phenotype-specificity, or transcript-consequence condition described by the clinical standard.

Some intragenic events require exon-level and transcript-level review beyond the automated representation before stronger loss-of-function evidence can be assigned.

Family segregation and de novo status are not automatically inferred for structural variants by this module.

Clinical Review Checklist

Confirm the event and breakpoint uncertainty with the upstream caller and assay quality metrics.

Review affected transcripts, genes, regulatory regions, and the relevance of partial versus complete overlap.

Evaluate inheritance, segregation, phenotype fit, penetrance, and mosaicism outside the automated score where necessary.

Consider orthogonal confirmation before clinical reporting, particularly for imprecise or borderline calls.

Verify the recorded interpretation framework and distinguish an unclassified record from a benign result.

Input and Scope

Recognized VCF records, normalization rules, framework ownership, and unsupported cases.